SPECIAL REPORT:

Venetoclax with methylating

agent or low dose
cytarabine: Sofie's choice
Maria Kristina G. de Jesus, MD
YL I
INTRODUCTION
• Acute myeloid leukaemia is clinically, cytogenetically and molecularly
a heterogeneous disease. Considering that a median age of patients in
AML is 71 years, it is a disease of older patients.
• Data are gathered always not only from the randomized, phase III
studies, but also from the population-based studies and retrospective
international and national results of the treatment.
• Age is the dominant risk factor for most chronic diseases, but the
mechanisms through which ageing confers this risk are largely
unknown.
• As we age, our tissues accumulate an increasing number of somatic
mutations. When this process happens in the haematopoietic system,
a substantial proportion of circulating blood cells may derive from just
one mutated stem cell. This outgrowth, called ‘clonal haematopoiesis’,
is highly prevalent in the elderly population.
VENETOCLAX
VENETOCLAX + HMA
OBJECTIVE
• General Objective
• To present a comparison of three (3) chemoterapeutic regimen in a
diagnosed AML patient whom are not inegilible to receive standard
induction chemotherapy

Specific Objectives
• to discuss the mechanism of action of each regimen
• To compare the side effects, outcome and costing for each regimen
OBJECTIVE OF THE STUDY
Determination of improved the overall survival (OS) of patients compared with placebo
plus LDAC.

Secondary objectives were to compare the following measures between treatment arms:
• complete remission (CR); CR plus CR with partial hematologic recovery (CRh);
• CR plus CR with incomplete hematologic recovery (CRi);
• proportion of patients with CR/CRi and CR/CRh by initiation of therapy cycle 2;
• rate of transfusion independence; event-free survival (EFS);
• minimal residual disease (MRD),
• response rates and OS in the subsets of patients with mutations in NPM1, IDH1/2,
FLT3, or TP53;
PATIENTS
Patients were considered ineligible for intensive induction chemotherapy if they >75 years or age 18
to 74 years
• ECOG) performance status of 2 to 3,
• cardiac history of congestive heart failure requiring treatment or ejection fraction #50% or chronic
stable angina,
• diffusion capacity of the lung for carbon monoxide
• creatinine clearance 30 to ,45 mL/min,
• moderate hepatic impairment with total bilirubin .1.5 to 3.0 3 upper limit of normal, or any other
comorbidity that was physician judged to be incompatible with conventional intensive
chemotherapy.
• Patients with secondary AML with or without prior treatment with HMAs for myelodysplastic
syndrome
• Exclusion criteria included prior therapy for AML (except hydroxyurea before or during the first
cycle of study treatment) and any previous exposure to cytarabine for any indication.
 TRIAL DESIGN AND REGIMEN
Venetoclax dosing began at 100 mg on day 1 and increased stepwise over 4 days to
reach the target dose of 600 mg (100, 200, 400, and 600 mg); dosing was continued
at 600 mg per day from day 4 through day 28. In all subsequent 28-day cycles,
venetoclax was commenced at the target dose.
• For patients randomized to the placebo arm, placebo (identical appearance tablet)
was administered in the same fashion as venetoclax.
• For patients in both arms, LDAC (20 mg/m2) was administered by subcutaneous
injection once daily on days 1 to 10 in all cycles.
• Patients could continue receiving treatment until progression or until study
treatment discontinuation criteria were met
• Patients remained on study for OS assessment and follow-up, even if they initiated
additional lines of treatment.
OUTCOME SIDE EFFECT COST

• CR/CRi - 48% vs 13% • febrile neutropenia (32% vs 29%),

• CR - 27% vs 7% of patients neutropenia (46% vs 16%),
• Higher rates of remission - 4.7 months vs thrombocytopenia (45% vs 37%),
2.0 months anemia (25% vs 22%)
• Rates of transfusion independence - • (venetoclax plus
higher for patients treated with venetoclax • LDAC vs placebo plus LDAC) were:
plus LDAC, with 37% nausea (42% vs 31%),
• (Morphologic CR or CRi, 6% (8 of 143) of • hypokalemia (28% vs 22%)
those in the venetoclax arm and 1% (1 of • diarrhea (28% vs 16%), and
68) of those in the placebo arm had a flow constipation (18% vs 31%)
cytometric MRD level of <0.1% • Overall, a similar percentage of
patients in both arms had AEs
• Across all patient subgroups, those treated • leading to death (33 [23%] and 14
with venetoclax plus LDAC had increased patients [21%], respectively).
rates of remission (CR, CRi, CRh) compared • 30-day mortality rates - 13% (n 5
with those treated with placebo plus LDAC. 18) and 16% (n 5 11) in
• the venetoclax and placebo arms,
respectively
OUTCOME SIDE EFFECT COST
• Patient survival - longer median OS in those treated
with venetoclax vs placebo across most patient
subgroups, except those with mutant FLT3.
• FLT3 mutations (29 patients): 9 patients in the
placebo arm and 20 in the venetoclax arm
• 20 FLT3+ patients in the venetoclax arm -
• - 6 had coexisting NPM1 mutations (not treated, n =
1), and all 5 (100%) who received therapy achieved
CR/CRi
• - 4 FLT3+ patients without NPM1 mutations -
achieved CR/CRi, with a median OS of 2.2 months.
• - Median OS for patients with coexisting FLT3 and
NPM1 mutations was 10.2 months in the placebo
arm and not yet reached in the venetoclax arm.
CONCLUSION
Venetoclax plus LDAC demonstrated:
-a well-tolerated and manageable safety profile
-clinically meaningful benefits in OS, rates of remission, EFS, transfusion
requirements, and patient-reported outcomes, compared with LDAC
alone
-rapid induction of remission and favorable benefit-risk profile suggest
that the addition of venetoclax to LDAC may provide an important
treatment option for patients not suitable for intensive chemotherapy.
PATIENTS
Patients were considered ineligible for intensive induction chemotherapy if they >75 years or age 18 to
74 years
• ECOG) performance status of 2 to 3,
• cardiac history of congestive heart failure requiring treatment or ejection fraction #50% or chronic
stable angina,
• diffusion capacity of the lung for carbon monoxide
• creatinine clearance 30 to ,45 mL/min,
• moderate hepatic impairment with total bilirubin .1.5 to 3.0 3 upper limit of normal, or any other
comorbidity that was physician judged to be incompatible with conventional intensive chemotherapy.
• Patients with secondary AML with or without prior treatment with HMAs for myelodysplastic
syndrome
• Exclusion criteria included prior therapy for AML (Previous receipt of any hypomethylating agent,
venetoclax, or chemotherapy for myelodysplastic syndrome)
• Patients with a favorable cytogenetic risk according to the AML NCCN guidelines
TRIAL DESIGN AND REGIMEN
• Eligible patients were assigned, in a 2:1 ratio, either to the azacitidine–venetoclax
group or to the control group.
• TLS Prophylaxis were given
• Venetoclax was administered orally, once daily, with food.
• For mitigation of the tumor lysis syndrome during cycle 1, the dose of venetoclax
was 100 mg on day 1 and 200 mg on day 2; on day 3, the target dose of 400 mg
was reached and continued until day 28. In all subsequent 28-day cycles, the dose
of venetoclax was initiated at 400 mg daily.
• Patients in the control group received an oral venetoclax placebo according to the
same schedule. Patients in both groups received azacitidine at a dose of 75 mg per
square meter of body-surface area, subcutaneously or intravenously, on days 1
through 7 every 28-day cycle.
OUTCOME
Primary End Point
• Median overall survival -
14.7 months vs 9.6 months
SIDE EFFECT COST
• Grade 3 or higher
• thrombocytopenia - 45% vs 38%
neutropenia - 42% vs 28%
• febrile neutropenia - 42% vs 19%
• anemia - 26% vs 20%
• leukopenia - 21% vs 12%
• Gastrointestinal adverse events -
• nausea -44% vs 35%
• constipation - 43% vs 39%
• diarrhea - 41% vs 33%
• vomiting - 30% vs 23%
• Notable serious adverse events (grade
≥3)
• febrile neutropenia - 30% vs 10%
• Pneumonia - 16% vs 22%
• Tumor lysis syndrome was reported
during the ramp-up period (on days 1
through 3 when the dose of
venetoclax was increased - 3 vs 0
OUTCOME SIDE EFFECT COST

Secondary End Points • Mortality at 30 days - 7% vs 6%

• No differences were observed
• Composite complete remission was between the two treatment groups
achieved in 66.4% vs 28.3% with respect to quality-of-life
• Composite complete remission before measures.
the initiation of cycle 2 was achieved -
43.4% vs 7.6%
• Median time to first response (either
complete remission or complete
remission with incomplete
hematologic recovery) - 1.3 months vs
2.8 months
• Median duration of composite
complete remission - 17.5 months vs
13.6
• Complete remission - 36.7% vs 17.9%
• Duration of complete remission - 17.5
months vs 13.3 months
• complete remission plus complete
remission with partial hematologic
recovery - 64.7% vs 22.8%
OUTCOME SIDE EFFECT COST

• In patients with IDH1 or IDH2

mutations:
• Composite remission - 75.4% vs
10.7%
• (+) FLT3 mutations - 72.4% vs 36.4%
• (+) NPM1 - 66.7% vs 23.5%
• (+) TP53 - 55.3% vs 0%
• Complete remission, measurable
residual disease negativity - 23.4% vs
7.6%
• Median overall survival among
patients with de novo AML - 14.1
months vs 9.6 months
• Median overall survival among
patients with secondary AML - 16.4
months vs 10.6 months
• With intermediate cytogenetic risk:
median overall survival - 20.8 months
vs 12.4 months
• With poor cytogenetic risk:
• Median overall survival - 7.6 months
vs 6.0 months
OUTCOME SIDE EFFECT COST

• End point was reached before the

beginning of cycle 2 in 39.9% vs 5.5%
• Median time to first response - 1.0
month vs 2.6 months
• Duration of response - 17.8 months vs
13.9 months
• Incidence of post baseline transfusion
independence was higher among
patients in the azacitidine–venetoclax
• Median event-free survival - 9.8
months vs 7.0 months
• Composite complete remission who
had measurable residual disease of
less than 1 residual blast per 1000
leukocytes, overall survival at 24
months 73.6% vs 63.6%
• (+) IDH1 or IDH2 mutations at
baseline, overall survival at 12 months
- 66.8% vs 35.7%
CONCLUSION
Venetoclax plus Azacitidine demonstrated:
• effective treatment regimen that led to significant improvements in
the incidence of composite complete remission and overall survival.
• Unlike monitoring of patients who receive azacitidine alone, ongoing
attentiveness to the monitoring and management of
myelosuppression is key for patient safety with this combination
therapy
10-day decitabine with venetoclax for newly diagnosed
intensive chemotherapy ineligible, and relapsed or
refractory acute myeloid leukaemia: a single-centre,
phase 2 trial

Author links open overlay panelCourtney D DiNardo MD a †, Abhishek Maiti MBBS a b †, Caitlin R Rausch
PharmD c, Naveen Pemmaraju MD a, Kiran Naqvi MD a, Naval G Daver MD a, Tapan M Kadia MD a, Prof
Gautam Borthakur MD a, Maro Ohanian DO a, Yesid Alvarado MD a, Ghayas C Issa MD a, Guillermo Montalban-
Bravo MD a, Nicholas J Short MD a, Musa Yilmaz MD a, Prithviraj Bose MD a, Prof Elias J Jabbour MD a, Koichi
Takahashi MD a, Prof Jan A Burger MD a, Prof Guillermo Garcia-Manero MD a, Nitin Jain MD a…Prof Marina Y
Konopleva MD a
OBJECTIVE OF THE STUDY
Determination of overall response rate of 10day Decitabine +
Venetoclax

Secondary objectives
• Determination of safety and overall survival
TRIAL DESIGN AND REGIMEN
• Eligibility criteria included ECOG PS ≤3, WBC ≤10 x10 9/L, and adequate
organ function.
• Decitabine dose was 20 mg/m 2 IV daily on D1-10 until CR/CRi,
followed by 5-day cycles.
• Venetoclax was given on D1-28 in cycle 1 but was interrupted on C1D21
until count recovery if the D21 bone marrow (BM) had ≤5% blasts.
• Venetoclax dose was 400 mg PO daily or equivalent with concomitant
azole antifungals
• Venetoclax duration could be reduced to 14 to 7 days in subsequent
cycles in cases of prolonged myelosuppression.
OUTCOME SIDE EFFECT COST

The CR/CRi rate • infections with grade 3/4 neutropenia (40%)

• febrile neutropenia (29%)
• ND AML 83% • infection with unknown ANC (17%) grade 5
• untreated sAML - 65% events including infections with grade 3/4
neutropenia (n=6), infections with unknown ANC
• treated sAML - 40% (n=4), and renal failure
• R/R AML - 42%
• HR-MDS/CMML - 20%
Rates of negative measurable
residual disease (MRD) by flow
cytometry
• ND AML - 73%,
• untreated sAML - 53%
• treated sAML - 65%
• R/R AM - 58%
OUTCOME SIDE EFFECT COST
Median follow-up of 24.7 months -
Median OS
• ND AML - 16.2 mo
• untreated sAML - 10.7 mo
• treated sAML - 5.8 mo
• R/R AML - 7.8 mo
• HR-MDS/CMML - 10.1 mo
1-yr OS
• ND AML - 54%,
• untreated sAML - 41%
• treated sAML - 36%
• R/R AML - 41%
• HR MDS/CMML - 35%
Median RFS
• ND AML - 10.9 mo
• untreated sAML - 6.7 mo
• treated sAML was 11.4 mo
• R/R AML - 8.4 mo
OUTCOME SIDE EFFECT COST
• 44 pts underwent SCT after
achieving response including ND
AML (n=17), untreated sAML
(n=4), treated sAML (n=3), R/R
AML (n=16), and HR-MDS/CMML
(n=4).
• The 100-day post-SCT mortality
was 9% (n=4).
• Median OS after SCT in pts with
previously untreated AML was
31.1 mo and in previously treated
AML was 15.0 mo
CONCLUSION
Decitabine + Venetoclax demonstrated:
• An effective therapy for older pts with ND and R/R AML.
• Patients whom are elligible for SCT after response with DEC10-VEN
may offer long-term survival advantage in this older/unfit population
with both ND and R/R AML.